Understanding Herpes Simplex Virus Type 1 Versus Herpes Simplex Virus Type 2 Encephalitis After Neurosurgery: A Case Series and Literature Review

Abstract

Background:

Herpes simplex virus encephalitis (HSVE) is a rare post-operative infection that can be fatal if treatment is delayed. Herpes simplex virus type 1 (HSV-1) is a more common cause of encephalitis than herpes simplex virus type 2 (HSV-2), however, a significant overlap exists. The goal of this project was to understand the frequency and trend of HSVE after neurosurgery through a case series at our institution and in the literature with a focus on comparing HSV-1 versus HSV-2.

Patients and Methods:

A literature review of all published cases and case series of HSVE after neurosurgery was performed. Descriptive statistics comparing HSV-1 and HSV-2 encephalitis were computed. Data on demographics, symptoms, surgery, treatment, immunosuppression, imaging findings, steroids, and mortality were collected.

Results:

We identified 55 total cases of HSVE post-neurosurgery. These included 28 cases of HSV-1, 10 cases of HSV-2, and 17 cases of HSV-unspecified encephalitis. There were no differences in age, gender, symptoms, surgery, or latency between surgery and symptom onset between HSV-1 and HSV-2. Mortality was higher with HSV-1 versus HSV-2 although not statistically significant. The primary surgical indication varied substantially between HSV-1 and HSV-2.

Conclusions:

Herpes simplex virus encephalitis is often overlooked in the setting of encephalitis after surgery. A high index of suspicion is needed to prevent a delay in treatment.

Intracranial infection after neurosurgery is mainly caused by iatrogenic bacterial infections. Herpes simplex virus encephalitis (HSVE) is a rare post-operative infection that can be fatal if appropriate treatment is delayed. It is challenging to detect because symptomatology can be masked by the effects of steroids or post-operative recovery. Herpes simplex virus type 1 (HSV-1) is associated with encephalitis, whereas herpes simplex virus type 2 (HSV-2) is a predominant cause of aseptic meningitis. However, an overlap exists and less than 10% of cases with HSV-2 central nervous system (CNS) infections present with encephalitis rather than meningitis.¹ The goal of this project was to report all known published cases to date of HSVE after neurosurgery through a literature review. We have also performed a case series at our institution to supplement the existing data. The secondary goal was to trend HSV-1 versus HSV-2 encephalitis after neurosurgery and compare risk factors, presentation, and treatment.

Case Series

Case 1

A 69-year-old male underwent a right sphenoid meningioma resection. He had controlled diabetes mellitus type 2 and was without baseline cognitive impairment. He was initiated on a dexamethasone taper on post-operative day 1, beginning with dexamethasone 20 mg and levetiracetam. On post-operative day 3, he became lethargic and disoriented, following only a few simple commands. Head computed tomography (CT) revealed a right frontal extra-axial hematoma adjacent to the craniotomy with an 8-mm midline shift. He underwent evacuation and replacement of a bone flap with rapid neurologic improvement. His incision site was clean and intact.

On post-operative days 6–9, the patient became increasingly encephalopathic, febrile at 39.3°C, and with leukocytosis (21 K/uL). An electroencephalogram (EEG) revealed non-convulsive status epilepticus and he was managed with antiepileptics and intravenous antibiotic agents. On post-operative day 11, he remained febrile. Head CT revealed pneumocephalus. The patient underwent external ventricular drain placement. Intra-operative findings noted residual infarcted tumor. Cerebrospinal fluid (CSF) revealed 30/mm³ white blood cell (WBC) count, 41% lymphocytes ,and negative cultures. Pathology of residual tumor was negative for HSV. On post-operative day 13, repeat CSF noted 222/mm³ red blood cells (RBC) and 33/mm³ WBC. His dexamethasone was increased. On post-operative day 14, the patient developed multiple right-sided electrographic seizures, requiring a phenobarbital infusion. Repeat head CT noted hemorrhage in the right anterior temporal lobe with surrounding edema.

On post-operative day 17, CSF HSV-2 polymerase chain reaction (PCR) returned positive. Further examination revealed a penile ulcer and several foot lesions that were both HSV-2 PCR positive. Plasma quantitative HSV-2 PCR also returned positive at 5,500 copies. Liver function was normal and human immunodeficiency virus (HIV) screen was negative. Brain magnetic resonance imaging (MRI) revealed extensive right frontotemporal abnormality and asymmetric leptomeningeal enhancement. On post-operative day 22, five days after high-dose intravenous acyclovir was initiated, head CT demonstrated diffuse vasogenic edema of the right frontoparietal and temporal lobes with compression of the third and right lateral ventricle. Repeat CSF HSV PCR remained positive. On post-operative day 24, CSF revealed 8/mm³ WBC, 59% lymphocytes and 52/mm³ RBC. The patient ultimately died on post-operative day 29.

Case 2

A 26-year-old male with bipolar disorder was diagnosed with an astrocytoma after a year of frequent seizures. He was otherwise healthy and not taking steroids. On post-operative day 1 after cranial resection, dexamethasone was initiated with a taper. On post-operative day 7, the patient developed severe headaches, and his dexamethasone dose was increased. On post-operative day 8, he became confused and experienced a convulsive seizure. On post-operative day 12, the patient was febrile with a temperature of 39°C. Cerebrospinal fluid revealed 112/ mm³ WBC, 79% lymphocytes, 25/ mm³ RBC. On post-operative day 17, brain MRI revealed leptomeningeal and gyriform enhancement with edema involving the right frontoparietal lobes and less in the temporal lobes. Cerebrospinal fluid HSV PCR from post-operative day 13 and post-operative day 17 returned positive for HSV-2. Acyclovir was initiated on post-operative day 19 with clinical improvement.

Case 3

A 62-year-old male underwent a left transtemporal resection for a cerebellopontine angle tumor. He was otherwise healthy. The patient was initiated on dexamethasone 4 mg every 6 hours with a taper on post-operative day 1. He developed a CSF leak on post-operative day 7 and was given acetazolamide. On post-operative day 11, he developed headaches with fevers, followed by confusion on subsequent days. On post-operative day 16, the patient became hypotensive. A brain MRI revealed a left middle cerebellar peduncle infarct, but no abnormal signal in the temporal or frontal lobes. Cerebrospinal fluid on post-operative day 16 showed 475 WBC/mm³, 83% lymphocytes, 1/mm³ RBC, and the patient was initiated on acyclovir. Cerebrospinal fluid HSV-1 PCR returned positive. He had clinical improvement after two weeks of acyclovir.

Patients and Methods

In addition to a case series, a review of the literature was performed to identify all published cases of HSVE post-neurosurgery. A PubMed search was conducted utilizing the search terms HSVE, HSV encephalitis, herpes simplex, and neurosurgery. Study results were screened for cases that described HSVE after neurosurgery. Patients with a positive CSF HSV PCR and with abnormal symptoms after surgery were included. We excluded HSVE based only on clinical diagnosis without microbiologic or histopathologic evidence. Coinfection with bacterial meningitis cases were also excluded. Descriptive statistics comparing HSV-1 and HSV-2 encephalitis were performed using STATA 17.² The primary outcome was CSF HSV type, a binary variable equal to HSV-1 or HSV-2; thus, we excluded CSF HSV-unspecified in the final statistical analysis. Data on gender, age, symptoms, surgery and primary indication, immunosuppression status, brain imaging findings, steroid receipt, whether HSV infection was present elsewhere and mortality were collected. Both χ² and Fisher exact tests were used for categorical variables, and t-tests for continuous variables. A p value less than 0.05 indicated statistical significance.

Results

In total, we identified 52 published cases of HSVE post-neurosurgery that met our inclusion criteria. Supplementary Table S1 includes the results of the aggregated data of the 55 total cases of HSVE post-neurosurgery including three identified with our case series. These include 28 cases of HSV-1, 10 cases of HSV-2, and 17 cases of HSV-unspecified encephalitis post-neurosurgery.

Descriptive statistics are summarized in Table 1. Patients with HSV-1 were younger (males, 35; females, 40) versus those with HSV-2 (males, 49; females, 57), although not statistically significant. Gender was similar in both groups. Mortality was higher with HSV-1 (10/28) versus HSV-2 (2/10), although not statistically significant. Only three patients were immunosuppressed, of whom one died from HSV-1³; the other two immunosuppressed patients had HSV-unspecified encephalitis.^4,5 Most patients received post-operative steroids in both groups. The most frequent symptom leading to a lumbar puncture (LP) was confusion followed by fever, similarly in both groups. The median latency between surgery and symptom onset was not significantly different between both groups (7.5 vs. 7.0 days). This was observed before and after removing an outlier of 120 days in the HSV-2 group, while maintaining values at 30 days (n = 2) and 42 days (n = 1).

Table 1.

Baseline Characteristics by CSF HSV Type (n = 38)

	HSV-1 (n = 28)	HSV-2 (n = 10)	p ^*
Descriptive characteristics (no. of HSV unspecified)^a
Gender (14)			0.38
Male (n = 17)	14	3
Female (n = 21)	14	7
Age, mean (SD), y	37.3 (23)	51.2 (19.2)	0.1
Male (n = 17)	34.6 (23.1)	49.3 (21.7)	0.33
Female (n = 21)	40 (23.5)	56.5 (17.4)	0.14
Primary surgical indication (17)			0.017
Craniopharyngioma (n = 3)	0	3
GBM (n = 7)	6	1
Epilepsy (n = 9)	8	1
Acoustic neuroma (n = 3)	3	0
Meningioma (n = 4)	2	2
Other^b	9	3
Primary surgery (16)			0.55
Resection (n = 19)	12	7
Lobectomy (n = 3)	3	0
Decompressive craniectomy (n = 3)	2	1
AH (n = 2)	2	0
Debulking (n = 1)	1	0
Ablation (n = 2)	2	0
Post-operative steroids (5)			0.54
No (n = 2)	2	0
Yes (n = 21)	15	6
POD symptom onset, median (IQR), d	7.5 (4)	7.0 (6)	0.6
POD of acyclovir, mean (SD), d	14.4 (9.7)	22.9 (14.2)	0.1
Immunosuppressed (15)			0.76
No (n = 28)	21	7
Yes (n = 1)	1	0
Extra-CNS HSV (2)	2	2	—
Mortality (14)			0.38
No (n = 25)	18	7
Yes (n = 12)	10	2

Bolded p value indicates significance (p < 0.05).

Table does not include 17 cases of HSV unspecified. ^b“Other” was not included in the p value generation

HSV = herpes simplex virus; CSF = cerebrospinal fluid; POD = postoperative day; GBM = glioblastoma multiforme; IS = immunosuppression; ACV = acyclovir; AH = amygdalohippocampectomy; SD = standard deviation; CNS = central nervous system; IQR = interquartile range.

The primary surgical indication varied between HSV-1 and HSV-2 where a diagnosis of craniopharyngioma was seen only in HSV-2 whereas glioblastoma multiforme and epilepsy were predominantly seen in HSV-1.

We identified eight cases with CSF lymphocytes under 50%, regardless of LP timing (post-operative day 2–11; Supplementary Table S1). Gong et al.⁶ described a case of HSV-1 encephalitis with post-operative day 2 LP of 360/mm³ WBC, 7% lymphocytes and positive CSF HSV PCR; however, this was followed by post-operative day 11 LP with 53/mm³ WBC, 68% lymphocytes and negative CSF HSV PCR. Perry et al.⁷ described a case of HSV-2 encephalitis with post-operative day 5 LP of 0/mm³ WBC, followed by post-operative day 12 LP of 98% lymphocytes. This pattern suggests that pleocytic lymphocytosis may not be present in the initial infectious period after symptom onset.⁸ Nevertheless, several cases in which an LP was performed late after symptom onset, e.g., post-operative day 10, demonstrated minimal CSF lymphocytosis.^9–13

Discussion

Our review shows that HSVE after neurosurgery is a frequently missed or delayed diagnosis and may be more common than clinicians realize, with HSV-1 being more frequent than HSV-2. The diagnosis of HSVE should be considered as a potential complication of neurosurgery, particularly if the patient has recent re-activation of HSV or if the patient is manifesting extra-CNS HSV symptoms, as was seen in case 1 of our case series. The patient's clinical picture of multiple seizures refractory to antiepileptic therapy along with lymphocytic pleocytosis and positive CSF HSV-2 PCR was consistent with HSV-2 encephalitis. He exhibited disseminated disease with an HSV-2 confirmed genital and left foot lesion and HSV viremia. Re-activation with dissemination was thought to be caused by post-operative immunosuppressive steroid doses and neurosurgic intervention. The patient had no evidence for other acquired immunodeficiency. His interval increase in vasogenic edema was likely a result of HSV progression. Corticosteroids may have a role in decreasing the activation of several inflammatory pathways and have been shown to be of benefit in animal models for HSVE.¹⁴ However, there is no robust randomized control trial to date that has identified benefit or harm conclusively.

As with several of the cases seen in the literature, case 2 in our case series improved with therapy despite acyclovir initiated more than one week after symptom onset with confusion and seizures. Case 3 had a less convincing diagnosis of encephalitis given the brain MRI was without abnormalities and arterial hypotension being another possible explanation for his presentation. Regardless, this patient had lymphocytic pleocytosis and a positive CSF HSV PCR thus demonstrating an atypical presentation of HSVE.

Our review and analysis did not reveal differences in age, gender, symptoms, surgery performed, or mortality between HSV-1 and HSV-2 encephalitis after neurosurgery. Few cases were discovered with immunosuppression.^3–5 We found that the latency between surgery and symptom onset was not statistically different in HSV-1 versus HSV-2, with the latter having four cases with a latency greater than 30 days. This suggests that there is no definite time frame, and the physician must consider HSVE as a potential diagnosis, even weeks after neurosurgery. This is not surprising as prior studies have shown that there are no clear differences in clinical presentation (not limited to the CNS) between HSV-1 and HSV-2.^15,16 Notably, it has been previously seen that racial differences account for a predominance of HSV-1 versus HSV-2 general infection.¹⁵ This variable was not included in our study but might be worthwhile to consider in future research.

The exact cause of HSV reactivation after neurosurgery is not fully understood. Surgical manipulation of the nerve or ganglion in which the virus is dormant, the stress factor from surgery itself, and the peri-operative use of steroids may contribute to viral reactivation.¹ It can be caused by re-activation of a previous CNS infection.¹⁷ Interestingly, only four published cases reported extra-CNS HSV infections occurring at the time of diagnosis.^3,18–20 These cases along with case 1 emphasize the importance of identifying skin, oral, and genital lesions that may prompt the provider to consider HSVE before a confirmed diagnosis.

Limitations of this study include missing data, including 17 cases of HSV-unspecified encephalitis after neurosurgery. Several covariables also contained missing data and this is shown in Table 1. This resulted in a small power with statistical computations. Case 3 in our case series was included based on the positive HSV CSF PCR; however, this case had a less convincing diagnosis of encephalitis given the brain MRI was without sustentorial abnormalities, there was no EEG, and arterial hypotension being another possible explanation for his presentation. This review included patients only with positive CSF HSV PCR and abnormal symptoms after surgery; thus, we excluded post-neurosurgical patients who were asymptomatic and recovered without complications. As such, given the lack of comparison to potentially benign cases of HSVE, we are unable to make a conclusion about the severity of HSVE.

Conclusions

Although it might be overlooked and underdiagnosed after surgery, a high index of suspicion is needed to prevent a delay in diagnosis of HSVE. Although HSV-1 is a more frequent cause of encephalitis following neurosurgery versus HSV-2, we did not find a difference in risk factors or clinical features. A thorough examination may reveal extra-CNS lesions providing diagnostic clues. Early treatment is crucial to avoid permanent neurologic deficit.

Footnotes

Authors' Contributions

Conceptualization: Kazanji. Methodology: Kazanji. Manuscript editing and finalization: Kazanji. Manuscript editing and review: Benvenuto, Rizk. Data curation: Kazanji, Benvenuto, Rizk. Analysis: Kazanji, Benvenuto.

Funding Information

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Author Disclosure Statement

All authors declare that they have no competing interests or conflicts of interests.

Supplementary Material

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